Chronic arterial occlusive diseases indicate diseases characterized by peripheral blood flow disturbances and are represented by arteriosclerosis obliterans and thromboangiitis obliterans. For symptoms of blood flow disturbances, the Fontaine's classification is applied to determine their severity of the diseases and treatment methods. According to this classification, they are divided into stage I: rhigosis or numbness at legs, stage II: intermittent claudication, stage III: rest pain, and stage IV: ulceration. At present, many patients complain of intermittent claudication, and the number of patients is increasing year after year.
Intermittent claudication is a symptom common to chronic arterial occlusive diseases, especially to arteriosclerosis obliterans or thromboangiitis obliterans, all of which are associated primarily with chronic obstructions of large arteries of legs, and means a state in which upon muscle work, ischemia of leg muscles occurs and continuation of walking becomes difficult due to a dull pain, numbness or the like caused by the muscle ischemia, but a rest makes it possible to resume walking. It is considered to be a main cause that at a hypertrophic part of a tunica intima resulted from arteriosclerosis of a large artery in a leg, a thrombus is formed with expulsion of the tunica intima, hemorrhage, ulceration of the tunica intima or the like as an impetus, leading to obstruction of a lumen, and an ischemic disturbance occurs at a periphery of the large artery [Itoh, M., et al., Geriatric Medicine, 33, 857-880 (1995)].
In a patient with intermittent claudication, vascular endothelial cells have been damaged by arteriosclerosis, or often by his additional diseases such as hypertension, hyperlipidemia or diabetes. Adhering and aggregating ability for platelets has therefore been potentiated at the damaged site, and as a result of platelet aggregation, various vasoconstrictors containing serotonin are released, leading to further potentiation of vasoconstriction. There is hence an outstanding demand for drug capable of inhibiting both platelet aggregation and vasoconstriction at the same time and moreover, of acting specifically to the site of a lesion, especially having a potency profile particularly suited for the improvement of intermittent claudication.
In recent years, some compounds have been disclosed as potent therapeutic drugs for intermittent claudication. However, none of them are satisfactory in potency, effective duration, toxicity and side effects, or such potency profile as mentioned above.
As is appreciated from the foregoing, it is the current circumstance that practically no suitable drug is available for the treatment or improvement of intermittent claudication, and development of drug having high effectiveness is desired [William, R. H., Vascular Medicine, 2. 257-262 (1997)].
Accordingly, an object of the present invention is to provide a drug for treating or improving intermittent claudication, which can satisfy characters in potency, effect duration, toxicity and side effects, and potency profile. Another object of the present invention is to provide a preventive or therapeutic drug for chronic arterial occlusive diseases, arteriosclerosis obliterans or thromboangiitis obliterans.